Next-generation sequencing of ABCA4: High frequency of complex alleles and novel mutations in patients with retinal dystrophies from Central Europe
| Autor: | Jacek P. Szaflik, Kamil Szulborski, Jerzy Szaflik, Anna M. Ambroziak, Magdalena Korwin, Piotr Stawiński, Dominika Oziębło, Aneta Ścieżyńska, Monika Ołdak, Rafał Płoski, Maciej R Krawczyński |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Adolescent DNA Mutational Analysis Population ABCA4 Single-nucleotide polymorphism Biology Polymerase Chain Reaction Young Adult 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Gene Frequency Retinal Dystrophies Genetic variation Prevalence medicine Humans Allele education Allele frequency Exome Alleles Genetics education.field_of_study Genetic Variation DNA medicine.disease Sensory Systems Pedigree Europe Stargardt disease Ophthalmology Phenotype 030104 developmental biology Mutation 030221 ophthalmology & optometry biology.protein ATP-Binding Cassette Transporters Female |
| Zdroj: | Experimental Eye Research. 145:93-99 |
| ISSN: | 0014-4835 |
| DOI: | 10.1016/j.exer.2015.11.011 |
| Popis: | Variation in the ABCA4 locus has emerged as the most prevalent cause of monogenic retinal diseases. The study aimed to discover causative ABCA4 mutations in a large but not previously investigated cohort with ABCA4-related diseases originating from Central Europe and to refine the genetic relevance of all identified variants based on population evidence. Comprehensive clinical studies were performed to identify patients with Stargardt disease (STGD, n = 76) and cone-rod dystrophy (CRD, n = 16). Next-generation sequencing targeting ABCA4 was applied for a widespread screening of the gene. The results were analyzed in the context of exome data from a corresponding population (n = 594) and other large genomic databases. Our data disprove the pathogenic status of p.V552I and provide more evidence against a causal role of four further ABCA4 variants as drivers of the phenotype under a recessive paradigm. The study identifies 12 novel potentially pathogenic mutations (four of them recurrent) and a novel complex allele p.[(R152*; V2050L)]. In one third (31/92) of our cohort we detected the p.[(L541P; A1038V)] complex allele, which represents an unusually high level of genetic homogeneity for ABCA4-related diseases. Causative ABCA4 mutations account for 79% of STGD and 31% of CRD cases. A combination of p.[(L541P; A1038V)] and/or a truncating ABCA4 mutation always resulted in an early disease onset. Identification of ABCA4 retinopathies provides a specific molecular diagnosis and justifies a prompt introduction of simple precautions that may slow disease progression. The comprehensive, population-specific study expands our knowledge on the genetic landscape of retinal diseases. |
| Databáze: | OpenAIRE |
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